PROJECT SUMMARY/ABSTARCT The increased use of amphetamine-type stimulants (ATS), which refer to the group of stimulants including methamphetamine (MA) and amphetamine, has become a major global health problem in recent years. There is also an increasing concern about the high rate of the non-medical use of prescription stimulants among adolescents. In this competing renewal of DA024070, an international collaborative study aimed to determine the effects of MA on the developing brain, we propose to extend our studies in ATS-using adolescents to evaluate a novel treatment strategy for this population. On the basis of preliminary findings identifying adolescent-specific brain and cognitive vulnerability to stimulant exposure and the neuroprotective properties of cytidine-5'-diphosphate choline (CDP-choline), we propose to conduct a 12-week, randomized, double-blind, placebo-controlled trial of CDP-choline in ATS-using adolescents. As outcome measures, multi-level assessments will be performed at molecular, neural circuitry, cognitive, and clinical levels. It will be determined whether CDP-choline administration, compared to placebo administration, will 1) repair ATS-induced neural cell damage within the target brain regions, which will be assessed using multinuclear magnetic resonance spectroscopic imaging, 2) improve cognitive deficits and normalize the relevant target neural circuits, which will be assessed using neuropsychological tests and multimodal imaging analyses including cortical thickness analysis, diffusion tensor imaging analysis, and network analysis, and 3) reduce ATS-taking behaviors, which will be assessed using a combination of urine monitoring and self-report of ATS use. This study will demonstrate that CDP-choline engages the treatment target and thereby provides clinical benefits to ATS-using adolescents. In the context of the unique opportunity to recruit a special population, such as ATS-using adolescents, in Seoul, South Korea, this project will be performed based on the international collaboration between Perry F. Renshaw at the Brain Institute, the University of Utah, UT, USA and In Kyoon Lyoo at the Ewha Brain Institute, Ewha W. University, Seoul, South Korea. We believe that this research proposal is highly responsive to the International Research Collaboration on Drug Abuse and Addiction Research Program Announcement (PA-12- 040) that encourages the utilization of unique resources or subject populations which would otherwise be difficult to access domestically. As is also acknowledged in the '2007 Distinguished International Scientist Collaboration Award' and '2008 International Program Award for Excellence [Collaborative Research]', our well established collaboration will contribute to the success of this proposal.